Despite the extensive amount of research and the relatively large number of drugs devoted to the treatment of heart disease, mortality from cardiovascular disorders remains alarmingly high. Cardiovascular deterioration is known to commence early in life and is progressive throughout. It has been said that about half the population by the age of 50 have about fifty percent occlusion of at least one coronary artery, while less than about one-fifth have entirely unoccluded arteries at this age, Rissanen, Advan. Cardiol., 4, 99 (1970).
The mechanism of action of various antiarrhythmic drugs generally is mediated by their effects upon the electrophysiological properties of cardiac muscle and conducting tissue. The electrical potential difference present in a heart muscle is created by ionic concentration differences across the membrane of the cardiac cell; the cardiac membrane being selectively permeable to different ionic species which pass through pores or channels. When the cardiac muscle is at rest, its interior is negatively charged due to a high intracellular concentration of non-diffusable large anions. During the action potential, the interior becomes positively charged relative to the exterior due to the sudden increase in sodium permeability resulting in the influx of positive charges. Then, until repolarization of the tissue takes place, the membranes are totally refractory to the passage of further sodium ions. The refractory period is quite long since repolarization is about 100 times slower than depolarization. Any drug which shortens the duration of the cardiac action potential thus necessarily shortens the refractory period and consequently increases the possibility of re-entrant rhythms under certain abnormal conditions. The refractory period would of course be prolonged if repolarization were delayed.
Various drugs have been used in the treatment of rhythm disorders. Quinidine, procaine amide, and lidocaine are perhaps among the best known and most widely used agents. All of such drugs act primarily by directly affecting membrane conductance so as to increase or decrease various ionic flows. A number of quaternary ammonium salts recently have been found useful in treating arrhythmia. Among such salts is a drug called bretylium (see U.S. Pat. No. 3,038,004). Bretylium is a salt of (o-bromobenzyl)ethyldimethylammonium cation. It has been shown to be effective in the treatment of disturbances of ventricular rhythm which are not successfully treated by other more conventional drugs, see Morgan et al., J. Pharm. Sci., 65, 467 (1976). Unfortunately, it possesses many adverse side effects including sympathomimetic and sympathomlytic effects.
Several investigators recently have been interested in developing quaternary ammonium compounds which are useful antiarrhythmic and antifibrillatory drugs which at the same time cause no adverse effects on the antonomic nervous system (see particularly Lucchesi et al., "Pharmacological Modification of Arrhythmias After Experimentally Induced Acute Myocardial Infarction" American Heart Association Monograph No. 47, December, 1975). The dimethyl quaternary ammonium salt of propranolol has demonstrated useful antiarrhythmic activity against a variety of experimentally induced cardiac arrhythmias, Schuster et al., J. Pharmacol. Exp. Ther., 184, 213 (1973) and Kniffen et al., J. Pharmacol. Exp. Ther., 187, 260 (1973).
An object of this invention is to provide certain phenylbutyl ammonium salts and phenylpropyl ammonium salts which are extremely potent in prolonging cardiac action potential duration. The compounds are thus useful for prolonging the refractory period in cardiac muscle and conducting tissue and thereby are useful in decreasing the vulnerability of the heart to re-entrant arrhythmias.